Project Summary Temporal lobe epilepsy is often associated with significant cognitive dysfunction, but the mechanisms underlying such dysfunction are not understood. In both human temporal lobe epilepsy and related models, neuronal loss occurs in selected populations of hippocampal neurons, and this cell loss could be associated with the learning and memory deficits. The effects of loss of each of the most vulnerable groups of neurons are of particular interest, and these neurons include mossy cells in the hilus of the dentate gyrus, hilar somatostatin (SOM) neurons, and SOM neurons in stratum oriens of CA1, the majority of which are oriens lacunosum-moleculare (OLM) neurons. It remains unclear how the loss of each cell type contributes to the reorganization of synaptic connections and alters the in vivo function of hippocampal circuits. The broad goal of this proposal is to determine the effects of selective ablation of each of these three groups of hippocampal neurons and associated axonal reorganization on electrophysiological and behavioral measures of cognitive function. To determine the effects of loss of each cell population, the neurons will be ablated separately through adeno-associated virus (AAV) expression of Cre-dependent diphtheria toxin A in mice with cell-type specific expression of Cre. Specific Aim 1 will test the hypothesis that selective ablation of each of the vulnerable groups of neurons will lead to unique patterns of reorganization of remaining populations of neurons. Cre-dependent transfection of eYFP in Cre-expressing mice will be used to identify changes in the axonal arborizations of remaining neurons and determine if aberrant synaptic circuits are created. Specific Aim 2 will test the hypothesis that mossy cell or hilar SOM neuron deletion, but not OLM neuron deletion, will induce desynchronization of dentate hilar neuron firing during locomotion. Silicon probe recordings of theta oscillations and multiple single-unit recordings of dentate hilar neurons will be used to determine whether mossy cell, hilar SOM interneuron, or SOM OLM deletion induces this desynchronization of dentate hilar neurons. Specific Aim 3 will test the hypothesis that OLM deletion, but not mossy cell or hilar SOM neuron deletion, will cause less precise (broadened) place related firing of CA1 pyramidal neurons. These studies will use calcium imaging of large populations of CA1 neurons in freely moving animals with custom-made miniaturized microscopes to determine which cell type is sufficient for degrading the precision of place field firing. This proposal combines the mutually complementary expertise of two laboratories to determine if loss of specific groups of neurons and related reorganization of hippocampal circuits can lead to changes in how large groups of neurons become synchronized and encode information, and thus contribute to cognitive dysfunction in epilepsy and related disorders.